PMID- 21691899 OWN - NLM STAT- MEDLINE DCOM- 20120327 LR - 20211020 IS - 1435-1803 (Electronic) IS - 0300-8428 (Linking) VI - 106 IP - 6 DP - 2011 Nov TI - Tumor necrosis factor receptor 2 signaling limits beta-adrenergic receptor-mediated cardiac hypertrophy in vivo. PG - 1193-205 LID - 10.1007/s00395-011-0196-6 [doi] AB - The in vivo role of TNF signaling in the genesis of beta-adrenergic receptor (beta-AR)-mediated cardiac hypertrophy is unknown. Wild-type (WT), TNF receptor 1 (TNFR1)-/- and TNFR2-/- mice were given isoproterenol (ISO, 12.5 mug/kg/h) or saline (SAL) for 1 or 7 days. In WT mice, 7 days of ISO yielded chamber/myocyte hypertrophy and hyperdynamic function without hypertension or fibrosis. WT ISO hearts exhibited an early (1 day) pro-inflammatory response with significant (p < 0.05) activation of nuclear factor (NF)-kappaB and activator protein 1 (AP-1) and upregulation of TNF, interleukin (IL)-1beta and IL-6, inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1), together with increased anti-inflammatory IL-10. This response diminished markedly by 7 days. As compared with WT ISO mice, TNFR1-/- ISO mice exhibited significantly (p < 0.05) less NF-kappaB and AP-1 activation, less IL-1beta, TNF, iNOS and MCP-1 upregulation, but greater IL-10 at 1 day. However, there were no differences in hypertrophy or contractility at 7 days. In contrast, TNFR2-/- ISO mice exhibited augmented NF-kappaB and AP-1 activation, increased IL-1beta and diminished IL-10 expression at 1 day, and significant exaggeration of hypertrophy and less contractile augmentation at 7 days. Moreover, TNFR2-/- mice exposed to tenfold higher ISO doses displayed significant mortality. TNF signaling contributes to beta-AR-mediated cardiac remodeling in vivo in a receptor-specific manner. Unopposed TNFR1 activation is pro-inflammatory, pro-hypertrophic and promotes functional decline. However, co-activation of TNFR2 during beta-AR stress is anti-inflammatory and counterbalances these deleterious effects. TNF modulatory strategies that maintain TNFR2 signaling may help prevent the detrimental long-term effects of beta-AR stimulation in the heart. FAU - Garlie, Jason B AU - Garlie JB AD - Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA. FAU - Hamid, Tariq AU - Hamid T FAU - Gu, Yan AU - Gu Y FAU - Ismahil, Mohamed Ameen AU - Ismahil MA FAU - Chandrasekar, Bysani AU - Chandrasekar B FAU - Prabhu, Sumanth D AU - Prabhu SD LA - eng GR - RR-024489/RR/NCRR NIH HHS/United States GR - HL-86787/HL/NHLBI NIH HHS/United States GR - HL-78825/HL/NHLBI NIH HHS/United States GR - HL-99014/HL/NHLBI NIH HHS/United States GR - R01 HL086787/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20110621 PL - Germany TA - Basic Res Cardiol JT - Basic research in cardiology JID - 0360342 RN - 0 (Adrenergic beta-Agonists) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Adrenergic, beta) RN - 0 (Receptors, Tumor Necrosis Factor, Type II) RN - L628TT009W (Isoproterenol) SB - IM MH - Adrenergic beta-Agonists/pharmacology MH - Animals MH - Blotting, Western MH - Cardiomegaly/*metabolism MH - Echocardiography MH - Enzyme-Linked Immunosorbent Assay MH - Isoproterenol/pharmacology MH - Male MH - Mice MH - Mice, Knockout MH - RNA, Messenger/analysis MH - Receptors, Adrenergic, beta/*metabolism MH - Receptors, Tumor Necrosis Factor, Type II/*metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects/*physiology EDAT- 2011/06/22 06:00 MHDA- 2012/03/28 06:00 CRDT- 2011/06/22 06:00 PHST- 2011/02/21 00:00 [received] PHST- 2011/06/13 00:00 [accepted] PHST- 2011/06/08 00:00 [revised] PHST- 2011/06/22 06:00 [entrez] PHST- 2011/06/22 06:00 [pubmed] PHST- 2012/03/28 06:00 [medline] AID - 10.1007/s00395-011-0196-6 [doi] PST - ppublish SO - Basic Res Cardiol. 2011 Nov;106(6):1193-205. doi: 10.1007/s00395-011-0196-6. Epub 2011 Jun 21.